Abstract In searching for the protein mediating the innate CD8+ cell non-cytotoxic anti-HIV response (CNAR) we have discovered that the external portion of CD137 (4-1BB) is a soluble protein that can induce a cellular antiviral state that prevents HIV replication. The full-length membrane-bound CD137 does not trigger this activity. The interaction of CD137 with its ligand, CD137L activates the cells expressing CD137, particularly T lymphocytes. The role of sCD137 is not known. sCD137 inhibits replication of all HIV isolates tested as well as polio, adenovirus, cytomegalovirus, and VSV. It is only active in human and primate cells and blocks virus replication at the transcription level. sCD137 can be found naturally in the blood of some individuals. Timing experiments have suggested that sCD137 can induce this antiviral state within a few hours after the exposure of human cells. Pilot studies have indicated that CD137L antibodies block the induction of the antiviral state by sCD137. Our hypothesis is that sCD137 interacts with the ligand CD137L on the cell surface to induce an intracellular antiviral state. Our proposed studies are aimed at confirming this hypothesis through #1, Using RNA-Seq, to determine the intracellular pathway responsible for the sCD137-induced antiviral state and #2, Using CRISPR- Cas9, to confirm that the sCD137/CD137L interaction is involved in inducing the antiviral state. These studies offer a new direction in antiviral immunotherapy that could be effective alone or in combination with antiretroviral therapy. Soluble CD137 could also be effective in shock and kill cure strategies in which the spread of the activated virus to uninfected cells could be controlled.